Dynamic Covalent Self-assembly Research Articles

Stimuli-Responsive Codelivery System Self-Assembled from in Situ Dynamic Covalent Reaction of Macrocyclic Disulfides for Cancer Magnetic Resonance Imaging and Chemotherapy.

Supramolecular self-assembly has gained increasing attention to construct multicomponent drug delivery systems for cancer diagnosis and therapy. Despite that these self-assembled nanosystems present surprising properties beyond that of each subcomponent, the spontaneous nature of co-self-assembly causes significant difficulties in control of the synthesis process and consequently leads to unsatisfactory influences in downstream applications. Hence, we utlized an in situ dynamic covalent reaction based on thiol-disulfide exchange to slowly produce disulfide macrocycles, which subsequently triggered the co-self-assembly of an anticancer drug (doxorubicin, DOX) and a magnetic resonance imaging (MRI) contrast agent of ultrasmall iron oxide nanoparticles (IO NPs). It showed concentration regulation of macrocyclic disulfides, DOX, and IO NPs by a dynamic covalent self-assembly (DCS) strategy, resulting in a stable codelivery nanosystem with high drug loading efficiency of 37.36%. More importantly, disulfide macrocycles in the codelivery system could be reduced and broken by glutathione (GSH) in tumor cells, thus leading to disassembly of nanostructures and intellgent release of drugs. These stimuli-responsive performances have been investigated via morphologies and molecular structures, revealing greatly enhanced dual-modal MRI abilities and smart drug release under the trigger of GSH. Moreover, the codelivery system conjugated with a targeting molecule of cyclic Arg-Gly-Asp (cRGD) exhibited significant biocompatibility, MR imaging, and chemotherapeutic anticancer effect in vitro and in vivo. These results indicated that in situ dynamic covalent chemistry enhanced the control over co-self-assembly and paved the way to develop more potential drug delivery systems.

Doubly chiral pseudopeptidic macrobicyclic molecular cages: Water-assisted dynamic covalent self-assembly and chiral self-sorting

<h2>Summary</h2> Taking advantage of the dynamic covalent chemistry approach, four different cages were synthesized by condensation of tripodal pseudopeptides with 4,4′-biphenyldicarboxyaldehyde. Whereas undesired products of polymeric nature were obtained in polar solvents, the [3+2] cryptand-type macrobicyclic architectures were obtained in excellent yields using chloroform as solvent, even at relatively high concentrations. The presence of two encapsulated water molecules may provide a positive template effect in the low polarity medium. The final macrobicycles display a combination of two types of chirality: d,l chirality due to the asymmetric α-C centers and P,M helical chirality. The homochiral helicity found for all the enantiomerically pure molecular cages indicates strong chirality induction by the asymmetric α-C. Besides, the self-sorting properties of the different chiral pseudopeptides have been studied, resulting in high-fidelity homo-self-sorting. DFT calculations point out that the self-sorting outcome may also be a direct result of the encapsulation of two water molecules within the cavity.

Dynamic Covalent Self-Assembly of Chloride- and Ion-Pair-Templated Cryptates.

While supramolecular hosts capable of binding and transporting anions and ion pairs are now widely available, self‐assembled architectures are still rare, even though they offer an inherent mechanism for the release of the guest ion(s). In this work, we report the dynamic covalent self‐assembly of tripodal, urea‐based anion cryptates that are held together by two orthoester bridgeheads. These hosts exhibit affinity for anions such as Cl−, Br− or I− in the moderate range that is typically advantageous for applications in membrane transport. In unprecedented experiments, we were able to dissociate the Cs⋅Cl ion pair by simultaneously assembling suitably sized orthoester hosts around the Cs+ and the Cl− ion.

Dynamic Covalent Self-Assembly of Chloride- and Ion-Pair- Templated Cryptates

Dynamic Covalent Self-Assembly of Chloride- and Ion-Pair- Templated Cryptates

Dynamisch kovalente Selbstassemblierung von Chlorid‐ und Ionenpaar‐templierten Kryptaten

AbstractWährend supramolekulare Wirte mit der Fähigkeit zum Binden und Transportieren von Anionen und Ionenpaaren heutzutage weit verbreitet sind, sind selbstassemblierte Architekturen immer noch selten, obwohl sie einen inhärenten Mechanismus für die Freisetzung der Gastionen bieten. In dieser Arbeit beschreiben wir die dynamisch kovalente Selbstassemblierung von dreizähnigen, Harnstoff‐basierten Kryptaten, die durch zwei Orthoester‐Brückenköpfe verbunden sind. Diese Wirte zeigen Affinitäten für Anionen wie Cl−, Br− und I− in moderater Höhe, die typischerweise vorteilhaft für Anwendungen im Membrantransport sind. In bislang beispiellosen Experimenten konnten wir das Ionenpaar Cs⋅Cl dissoziieren, indem wir simultan zwei passende Orthoester‐Wirte für das Cs+ and das Cl− Ion selbstassemblierten.

Dynamic covalent self-assembly of mechanically interlocked molecules solely made from peptides.

Mechanically interlocked molecules (MIMs), such as rotaxanes and catenanes, have captured the attention of chemists both from a synthetic perspective and because of their role as simple prototypes of molecular machines. Although examples exist in nature, most synthetic MIMs are made from artificial building blocks and assembled in organic solvents. Synthesis of MIMs from natural biomolecules remains highly challenging. Here we report on a synthesis strategy for interlocked molecules solely made from peptides—mechanically interlocked peptides (MIPs). Fully peptidic, cysteine-decorated building blocks were self-assembled in water to generate disulfide-bonded dynamic combinatorial libraries consisting of multiple different rotaxanes, catenanes and daisy chains as well as more exotic structures. Detailed NMR spectroscopy and mass spectrometry characterization of a [2]catenane comprised of two peptide macrocycles revealed that this structure has rich conformational dynamics reminiscent of protein folding. Thus, MIPs can serve as a bridge between fully synthetic MIMs and those found in nature.

Synthesis of Information-bearing Peptoids and their Sequence-directed Dynamic Covalent Self-assembly

Synthesis of Information-bearing Peptoids and their Sequence-directed Dynamic Covalent Self-assembly

Synthesis of Information-bearing Peptoids and their Sequence-directed Dynamic Covalent Self-assembly.

This protocol presents the use of Lewis acidic multi-role reagents to circumvent kinetic trapping observed during the self-assembly of information-encoded oligomeric strands mediated by paired dynamic covalent interactions in a manner mimicking the thermal cycling commonly employed for the self-assembly of complementary nucleic acid sequences. Primary amine monomers bearing aldehyde and amine pendant moieties are functionalized with orthogonal protecting groups for use as dynamic covalent reactant pairs. Using a modified automated peptide synthesizer, the primary amine monomers are encoded into oligo(peptoid) strands through solid-phase submonomer synthesis. Upon purification by high-performance liquid chromatography (HPLC) and characterization by electrospray ionization mass spectrometry (ESI-MS), sequence-specific oligomers are subjected to high-loading of a Lewis acidic rare-earth metal triflate which both deprotects the aldehyde moieties and affects the reactant pair equilibrium such that strands completely dissociate. Subsequently, a fraction of the Lewis acid is extracted, enabling annealing of complementary sequence-specific strands to form information-encoded molecular ladders characterized by matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS). The simple procedure outlined in this report circumvents kinetic traps commonly experienced in the field of dynamic covalent assembly and serves as a platform for the future design of robust, complex architectures.

Morphological Transformation between Orthogonal Dynamic Covalent Self-Assembly of Imine-Boroxine Hybrid Polymer Nanocapsules and Thin Films via Linker Exchange.

Orthogonal dynamic covalent self-assembly is used as a facile method for constructing polymer hollow nanocapsules (NCs) and thin films. The bifunctional precursor 4-formylphenylboronic acid is symmetrically installed with a boronic acid group for the boroxine linkage, and an aldehyde group for the Schiff base reaction which can react with twofold symmetry linkers ethylenediamine and para phenylenediamine to attain polymer NCs and nanosheets. Owing to the reversibility of the imine linkages, the mutual morphological transformation between polymer NCs and thin films via an amine-imine-exchange strategy is successfully achieved. Multiple reversible covalent bonds allow the control the release of the load in polymer NCs using different techniques. This may be useful for designing stimulus-responsive smart materials.

Discrete boronate ester ladders from the dynamic covalent self-assembly of oligo(phenylene ethynylene) derivatives and phenylenebis(boronic acid)

Reversible boronate ester chemistry enables the controlled, dynamic self-assembly of olig(phenylene ethynylene)s into highly conjugated ladder frameworks.

Self-templated synthesis of an orthoformate in,in-cryptand and its bridgehead inversion by dynamic covalent exchange.

We report the template-free dynamic covalent self-assembly of a small orthoformate cryptand, which appears to be driven by the formation of two sets of intramolecular, four-centre hydrogen bonds. In contrast to their nitrogen-bridgehead counterparts, orthoformate cryptands do not spontaneously invert, but require dynamic covalent exchange to do so.

Dynamic Covalent Self-Assembly Based on Oxime Condensation.

Oxime, whose dynamic nature was reported to be switchable between ON/OFF by tuning the acidity, is employed in a novel type of dynamic covalent approach that is amenable to use in water for self-assembly of purely organic molecules with complex topology. In strongly acidic conditions, the dynamic nature of oxime is turned ON, allowing occurrence of error-checking and therefore a catenane and a macrocycle self-assembled in high yields. In neutral conditions, oxime ceases to be dynamic, which helps to trap the self-assembled products even when the driving forces of their formation are removed. We envision that this switchable behaviour might help, at least partially, to resolve a commonly encountered drawback of dynamic covalent chemistry, namely that the intrinsic stability of the self-assembled products containing dynamic bonds, such as imine or hydrazone, are often jeopardized by their reversible nature.

High-Throughput Assay for Enantiomeric Excess Determination in 1,2- and 1,3-Diols and Direct Asymmetric Reaction Screening.

A simple and efficient method for determination of the yield, enantiomeric/diasteriomeric excess (ee/de), and absolute configuration of crude chiral diols without the need of work-up and product isolation in a high throughput setting is described. This approach utilizes a self-assembled iminoboronate ester formed as a product by dynamic covalent self-assembly of a chiral diol with an enantiopure fluorescent amine such as tryptophan methyl ester or tryptophanol and 2-formylphenylboronic acid. The resulting diastereomeric boronates display different photophysical properties and allow for fluorescence-based ee determination of molecules containing a 1,2- or 1,3-diol moiety. This method has been utilized for the screening of ee in a number of chiral diols including atorvastatin, a statin used for the treatment of hypercholesterolemia. Noyori asymmetric hydrogenation of benzil was performed in a highly parallel fashion with errors <1 % ee confirming the feasibility of the systematic examination of crude products from the parallel asymmetric synthesis in real time and in a high-throughput screening (HTS) fashion.

Long, self-assembled molecular ladders by cooperative dynamic covalent reactions

The dynamic covalent self-assembly of peptoid-based oligomers bearing n complementary functional groups yields molecular ladders with n covalent rungs.

ChemInform Abstract: Let′s Sort It Out: Self‐Sorting of Covalent Organic Cage Compounds

AbstractReview: [30 refs.

Let’s Sort It Out: Self-Sorting of Covalent Organic Cage Compounds

Dynamic covalent self-assembly of small and rigid precursors into cage-type architectures can serve as a powerful strategy for the formation of molecular porous units. In order to enhance the functionality of suchlike nanostructures, formation of complex multicomponent assemblies with high spatial precision, and on-demand control of both reversible assembly and disassembly is highly desirable. Here we highlight some of our most recent achievements on the size-specific synthesis and self-sorting properties within a series of covalent organic cage compounds and the stimuli-responsive assembly of supramolecular cages assembled by boron–nitrogen dative bonds. 1 Introduction 2 Self-Sorting of Covalent Organic Cages 3 Stimuli-Responsive Cages 4 Conclusion and Outlook

Small Is (also) Beautiful: Dynamic Covalent Self-Assembly of Cryptates

Cryptands can be seen as the smallest three-dimensional molecular cages still capable of accommodating (ionic) guests. We have recently realized the first dynamic covalent self-assembly of a monometallic cryptate, whose template synthesis and unique structure crucially rest on orthoester bridgeheads [Nat. Commun. 2015, 6, 7129]. In this Synpacts article, I discuss selected aspects that led to this discovery and I attempt to put the study into the context of recent trends in the self-assembly of larger molecular cages. 1 Introduction 2 Dynamic Covalent Self-Assembly of Orthoester Cryptates 3 From Covalent to Metallosupramolecular to Dynamic Covalent Synthesis 4 Orthoester Cryptates as Tiny Self-Assembled Cages 5 Conclusions

Determination of enantiomeric excess in amine derivatives with molecular self-assemblies.

We report the first fluorescence-based assay for the rapid determination of the ee value of amines, amino alcohols, and amino acid esters. The method uses the self-assembly of 2-formylphenylboronic acid with a chiral diol and a chiral amine or derivatives (of unknown chirality) to produce two diastereomeric iminoboronates that differ in their fluorescence intensity and polarization. The approach allows for the accurate determination of the ee value of chiral amines with errors of just 1-2%. We believe that this application of orthogonal dynamic covalent self-assembly in the determination of the enantioselectivity will lead to the development of high-throughput procedures for the determination of chirality.

Boronic Acid-Terminated Polymers: Synthesis by RAFT and Subsequent Supramolecular and Dynamic Covalent Self-Assembly

Well-defined homopolymers and block copolymers with boronic acid-functional end groups were prepared by reversible addition−fragmentation chain transfer (RAFT) polymerization and subsequently investigated for the potential to undergo model supramolecular and dynamic covalent self-assembly in aqueous and organic media. By employing a boronic acid-functionalized RAFT chain transfer agent, end-functional polymers were prepared without recourse to postpolymerization functionalization. The polymerizations of styrene, N,N-dimethylacrylamide, and N-isopropylacrylamide all led to homopolymers of controlled molecular weight that were capable of subsequent chain extension to form well-defined block copolymers. The amphiphilic and stimuli-responsive block copolymers were capable of self-assembly into micellar aggregates. Quantitative retention of the boronic acid chain termini during polymerization was spectroscopically demonstrated, and two types of dynamic covalent transformations involving these moieties were inv...

Programmed Dynamic Covalent Assembly of Unsymmetrical Macrocycles

Unsymmetrical shape-persistent macrocycles have been prepared from diphenylacetylene monomers using imine formation and metathesis. A sequence-directed approach, in which each monomer is uniquely labeled by its N-donor/C-donor sequence, has been used to control the self-assembly and makes possible an added level of complexity in the final structures. To illustrate the potential of this strategy, a series of macrocycles with different side-chain substitution patterns have been prepared, including monofunctionalized and Janus-type structures. We believe this to be the first example of sequence control of dynamic covalent self-assembly and that it will enable the fully covalent synthesis of more complex nanostructures.